Until recently, neutrophils have been considered to be end-differentiated cells that represent a front-line of cellular host defense, but with little or no ability to modulate the inflammatory responses of other cells. However, it has become clear that neutrophils can release certain cytokines and that altering neutrophil function or number with GCSF can have profound effects on the systemic inflammatory response induced by endotoxin or sepsis. The mechanisms by which neutrophils alter inflammatory responses in a general manner are not well defined but appear to be caused by more than simple antibacterial or antitoxin effects. Our work is focused on examining the mechanisms by which neutrophils effect monocyte/macrophage function and, endothelial cell function. We are also collaborators with Dr. Malech (NIAID) to examine these effects in patients with chronic granulomatous disease and in volunteers given GCSF. We have found that neutrophils can downregulate cytokine production by other cells via a mechanism that requires direct cell-to-cell contact and they can upregulate cytokine production through a soluble factor. Ex vivo studies using a whole blood TNF assay in GCSF stimulated normal volunteers shows that neutrophil number an state of activation has a profound effects on cytokine production. The regulation of the inflammatory response by neutrophils may be an important regulatory mechanism that may represent a new therapeutic target for treating sepsis.